Whenshould insulin therapy be initiated?Thisquestion will arise at a point in the management of patients with type 2diabetes mellitus, a progressive and chronic disease. The answer is notstraight forward. It leaves room for controversy. Oral medications aretraditionally introduced in stepwise manner with insulin reserved as the finalstep in the management of type 2 diabetes mellitus. This may take up to 10 – 15years after diagnosis before insulin is finally introduced. The fears ofpainful injections, weight gain and hypoglycaemia militates against earlyinitiation of insulin by both the physician and the patients13,14.

Negative beliefs about insulin treatment and other socio-cultural factors alsoaffect the acceptance of patients to accept insulin14, 15. Thispredisposes the patient to long term complications due to exposure to manyyears of uncontrolled hyperglycaemia16. This therefore calls forproactive approach to treatment failure. Lowering glycaemia improves insulinresistance as well as insulin secretion17. Early initiation ofinsulin therapy in newly diagnosed patient with type 2 diabetes mellitusrestores and maintains ?-cell function17. We advocate that insulinshould be initiated when stepwise approach failed to achieve the target HbA1Cof <7%18. This initiation should be swift when the HbA1C <7%is not achieved at 2-3 months of maximally dosed dual oral therapy.

Forpatients intolerant to one or more oral glucose lowering agents and who do notachieve glycaemic control with oral monotherapy, as well as those with apersonal preference, earlier initiation of insulin is indicated. It is noteworthythat rapid addition of insulin therapy is supported by numerous studies showingimproved treatment satisfaction and quality-of-life for type 2 diabetic patientswho had started using insulin19,20.  In what way should insulin therapy be initiated?Goodglycaemic control was achieved in majority of patients with type 2 diabetesmellitus in the ‘treat-to-target’ clinical trials when basal insulin was addedto their oral anti diabetic agents21-23.

It should however be notedthat the benefit of the long acting insulin analogues is in the reduction ofnocturnal hypoglycaemia24. According to the ADA/EASD algorithm forthe management of type 2 diabetes, insulin could be initiated with eitheronce-daily NPH insulin or a long acting insulin analogue18. Ameta-analysis that included six randomized comparisons of NPH and glarginefound event rates for self-monitoring of blood glucose (SMBG) confirmed symptomatichypoglycaemia  <65mg/dl of only 138and 91 events per 100 patient-years for these insulins, respectively, ininsulin-naive type 2 diabetic patients who achieved an A1C of 7.0%25.The NPH, insulin glargine and determir have been used as basal insulin toachieve glycaemic control in type 2 diabetes patients.

As desirable as this maybe, the cost implication of the newer insulins to the patient should not belost on the physicians. In Africa (and in Nigeria), the cost of insulin hasbeen a barrier to the acceptance of insulin therapy aside from socio-culturalissues15. The NPH is cost effective and insulin therapy in type 2diabetes can be initiated with NPH. The other issue to be considered is thefrequency of dosing for basal insulin. In a “treat-to-target” trial withtwice-daily detemir administration, an end point A1C of 6.8% was reached.

22In other studies, a second daily detemir injection was required in 34–55% ofstudy subjects because of pre-dinner hyperglycaemia or nocturnal hypoglycaemia.23,26  In the only reported trialthat investigated the efficacy of once-daily insulin detemir, A1C remained abovethe currently recommended glycaemic goal with an end point level of 7.4%, bothfor NPH insulin and detemir, 27 compared with an end of study A1C<7.0% with once-daily glargine and NPH in the original Treat-to-Target Trial.21Inthe ACCORD study,5 the finding of increased mortality in theintensive glucose lowering therapy group will probably deter some practitionersfrom lowering glucose promptly.

The ACCORD study solely included patients athigh risk for cardiovascular disease, in whom low A1C levels were reached byusing up to four or five different classes of glucose-lowering drugs. Incontrast, in less selected patients treated with stable doses of one or twooral agents, simple titration algorithms targeting fasting plasma glucose ?100mg/dl (?5.6 mmol/l) can safely achieve A1C of 7.

0%. 21 An algorithm,which is patient-driven, with patients increasing their insulin dose by 2 or 3units every 3 days, as long as their fasting plasma glucose remains abovetarget, constitutes a practical approach that has been shown to be equally ormore effective than physician-led titration. 28,29 In the timing ofonce-daily basal insulin regimens, administration of NPH in the evening appearsto be superior to morning injection. 7,19 There are conflictingresults in the studies from studies examining the injection time of thelong-acting insulin analogs. When morning and evening injection of insulin glarginewere compared in one study, there was a greater reduction in HbA1c andnocturnal hypoglycaemia when insulin glargine was given in the morning30,whereas in another larger study with identical design no significant differencewas found in the timing31.

A morning administration of insulin detemirwas associated with lower glucose levels during the day and a trend toward a reducedrisk of nocturnal hypoglycaemia compared with evening injection27.What do all these mean? We can safely conclude from these discrepant data thatwhen nocturnal hypoglycaemia limits dose titration of evening detemir or glargine,administration in the morning could be attempted.Other options existfor initiation of insulin therapy. The treating to target in type 2 diabetes(4-T) study compared various options of insulin initiation.

Basal insulinintroduced at bedtime was compared with either biphasic insulin twice daily orprandial insulin before meals26. It was found that regimens using biphasic orprandial insulin reduced HbA1c to a greater extent than basal, butwere associated with greater risks of hypoglycaemia and more weight gain26.The HbA1c lowering with biphasic insulin is equivalent toPrandial insulin. However, there is greater weight gain and more hypoglycaemiathan with Basal insulin but less for both than with Prandial insulin26.Initiation with prandial insulin is not a first choice approach when initiatinginsulin in type 2 diabetes mellitus. Credence was lent to this in the study comparingonce-daily insulin glargine versus thrice daily insulin lispro in insulin-naivepatients32. Thus addition of once basal insulin will reducefrequency of injection and promote acceptability by patients of insulininitiation. Combination of basal insulin with oral agents have been shown tominimize adverse effects of insulin therapy (i.

e. hypoglycaemia and weightgain)33. Combination of insulin with metformin is indeed associatedwith better glycaemic control, fewer hypoglycaemic events, and less weight gainthan treatment with insulin alone33. Therefore, metformin should becontinued when patients are initiated on insulin therapy (i.e., providing thereare no intolerable side effects).


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